'Cognitive control' describes the ability to configure, maintain, and adjust sets of processing strategies (task-sets), which underpins flexible, goal-directed behavior. The overarching goal of this proposal is to improve our understanding of the neural mechanisms mediating this behavioral flexibility. This represents a central challenge in the neurosciences that bears major clinical relevance, as many psychiatric and neurological conditions are characterized by impaired cognitive control. Our general strategy for achieving this goal is to fractionate the multifarious concept of cognitive control into experimentally tractable component processes, and to harness behavioral, neuroimaging, and neuro-disruptive techniques to probe their neural underpinnings and interrelations. As a point of departure we focus on conflict-driven control ('conflict adaptation'), a component mechanism of cognitive control that serves the function of task-set maintenance. Here, the monitoring of processing conflicts, arising from simultaneous activation of incompatible stimulus or response representations, is thought to provide a signal for reinforcing the top-down biasing processes that comprise the current task-set, thus ensuring that levels of biasing remain commensurate with task difficulty. We pursue two specific aims: first, to gain a more profound understanding of the neural mechanisms underlying conflict adaptation itself, and second, to position this conflict-driven control mechanism within the wider framework of other types of control processes that, in combination, facilitate flexible behavior. Two studies will address the first aim. Study 1.1 will examine the hypothesis that conflict-driven control is organized in a parallel architecture of multiple conflict adaptation loops, which resolve different types of conflict independently. For this purpose, we will define neural substrates of conflict adaptation to independently varied sources of conflict, using functional magnetic resonance imaging (fMRI), followed by fMRI-guided transcranial magnetic stimulation (TMS), to test whether distinct sources of top-down control play dissociable causal roles in resolving different conflicts. Study 1.2 will closely characterize the time-course of conflict adaptation processes. To address the second aim, three additional studies will assess how conflict adaptation interacts with other component mechanisms of cognitive control. Study 2.1 pursues this goal by contrasting the transient conflict adaptation mechanism with a more sustained form of control, by combining fMRI with an orthogonal manipulation of phasic and tonic levels of conflict. Study 2.2 contrasts the reactive nature of conflict adaptation with proactively recruited control, derived from explicit cues regarding forthcoming conflict. Finally, study 2.3 examines the relation between neural mechanisms underlying conflict-driven reinforcement of task-set with those that mediate detection of task-change and task-set reconfiguration, in a conflict task-switching paradigm. This research program has the potential to significantly enhance our understanding of how the human brain supports flexible, goal-directed behavior, and to highlight possible failure modes in this ability. PUBLIC HEALTH RELEVANCE: The proposed research is designed to elucidate neural mechanisms of 'cognitive control', the ability to generate, maintain, and adjust sets of goal-directed processing strategies, which lies at the heart of the type of flexible behavior that distinguishes humans from other animals, including other primates. We pursue this goal by combining experimental tasks that tax various component processes of cognitive control to differing degrees with measurements of brain activity (and functional connectivity between brain regions), as well as with stimulation techniques that temporarily inhibit function in a specific brain region, so that we can pinpoint which aspect of cognitive control is mediated by which brain region (or which set of interacting brain regions). The knowledge gained from this work will enhance our understanding of how the healthy brain mediates flexible, goal-directed behavior, and will provide more precise ideas of how neural mechanisms of cognitive control might be disrupted in psychiatric and neurological conditions.